We have investigated the requirement of a phosphodiesterase (PDE) inhibitor for catecholamine stimulation of cyclic AMP levels in intact epithelial cells. A variety of PDE inhibitors were tested for their potency in causing inhbition of PDE. They were also tested for their ability to increase cyclic AMP levels when combined with isoproterenol. Given the limitations of comparing experiments with intact cells versus broken cell preparations, there is a good correlation between the ability of a compound to inhibit PDE and its ability to significantly increase cyclic AMP levels when combined with catecholamines. We have also studied hormone induced refractoriness and have found that although isoproterenol by itself does not increase cyclic AMP levels, it will induce refractoriness with a t1/2 of less than 2 min.; virtually identical to isoproterenol and MIX, which increases cyclic AMP levels by 30 fold. Studies on hormonally responsive normal (K-16) rat liver epithelial cells and nonhormonally responsive chemically transformed (W8) rat liver epithelial cells have revealed the W8 cells contain beta-receptors which are functionally uncoupled from adenylate cyclase.